Substituted pyridoxine-lactam carboxylate salts

ABSTRACT

The present invention provides salt adducts comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted, methods of their preparation, and pharmaceutical compositions and medicaments comprising them. Salt adducts of the invention and compositions comprising them may be used to in the treatment of diseases or disorders associated with or inflicted by alcohol consumption.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a National Stage of International ApplicationNo. PCT/IL2009/000741, FILED Jul. 29, 2009, designating the UnitedStates and claiming priority from U.S. Provisional Patent ApplicationNo. 61/084,514, filed on Jul. 29, 2008, which is incorporated herein inits entirety by reference.

TECHNICAL FIELD

The present invention relates to salt adducts comprising at least onepyridoxine or a derivative thereof and at least one carboxylated 5- to7-membered lactam ring and uses thereof.

BACKGROUND OF THE INVENTION

Alcohol-induced liver diseases are a common disorder in moderncommunities and societies. For example, in Europe there are more than 45million individuals showing signs of alcohol-related damage such asliver disease and myopathies. Chronic alcohol consumption increaseshepatic accumulation of triglycerides and leads to hepatic steatosis,which is the earliest and most common response to severe alcoholintoxication.

Thus, severe alcohol intoxication is a serious disease that should betreated with medication in order to reduce the damage to the human bodyof the alcohol intoxicated individual. For example, alcohol intoxicationcan be treated with metadoxine (pyridoxineL-2-pyrrolidone-5-carboxylate). Metadoxine is a salt of thecorresponding anion of L-2-pyrrolidone-5-carboxylic acid(L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine(vitamin B6) (2), having the following structures:

WO 2008/066353 discloses the use of Metadoxine in the treatment ofalcohol intoxication either alone or in combination with other activeagents. WO 2008/066353 mentions that metadoxine does not inhibit theexpression and activation of an alcohol-induced cytochrome P450 2E1,which is the key enzyme involved in alcohol-induced toxicity. Thus, theuse of metadoxine may be limited.

Several studies have shown that in order to effectively treat alcoholintoxication, there is a need for a relatively high daily dose (ca. 900mg) administered intravenously (see, e.g., Lu et al. Chin. Med. J. 2007,120 (2), 155-168 and Shpilenya et al. Alcohol Clin. Exp. Res. 2002, 26(3), 340-346). These studies disclose side effects associated with theuse of metadoxine, including nausea and vomiting.

Thus, there exists a need in the art for effective and safe drugs fortreating alcohol intoxication and other associated diseases.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, salt adducts comprising atleast one pyridoxine or a derivative thereof and at least onecarboxylated 5- to 7-membered lactam ring, methods of their preparation,medicaments comprising those compounds, therapeutic treatments utilizingsalt adducts of the invention and uses thereof in the preparation ofpharmaceutical compositions.

In one aspect, the invention provides a salt adduct comprising at leastone positively charged moiety being a pyridoxine or a derivative thereofand at least one carboxylated 5- to 7-membered lactam ring, optionallyadditionally substituted; provided that when said carboxylated lactamring is an L-2-pyroglutamate (compound (1)), said positively chargedmoiety is other than pyridoxine (compound (2)).

In another aspect, the invention provides a pharmaceutical compositioncomprising a salt adduct of the invention.

In further aspect, the invention provides a use of a salt adduct of thedisclosure for the preparation of a pharmaceutical composition for thetreatment or prevention of a disease or disorder associated with orinflicted by alcohol consumption.

The invention also provides a use of a salt adduct of the invention forthe preparation of a pharmaceutical composition capable of shorteningthe half-life of ethanol in the blood of a subject.

In another aspect, the invention provides a method for treating orpreventing a disease or disorder associated with or inflicted by alcoholconsumption, comprising administering to a subject in need thereof aneffective amount of a salt adduct of the invention.

In a further aspect, the invention provides methods of shortening thehalf-life of ethanol in the blood of a subject, comprising administeringto a subject in need thereof an effective amount of a salt adduct of theinvention.

In another aspect, the invention provides a kit for reducing the effectof alcohol intoxication, comprising at least one container comprising asalt adduct of the invention, and instructions for use thereof.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides a salt adduct comprisingat least one positively charged moiety being a pyridoxine or aderivative thereof and at least one carboxylated 5- to 7-membered lactamring, optionally additionally substituted; provided that when saidcarboxylated lactam ring is an L-2-pyroglutamate (compound (1)), saidpositively charged moiety is other than pyridoxine (compound (2)).

As used herein the term “salt adduct” is meant to encompass a saltproduct of a direct addition of two or more distinct ions, wherein theoverall charge of the salt adduct is zero. In certain embodiments, thesalt adduct comprises one positively charged moiety having a singlepositive charge functional group (i.e., the positively charged moiety ischarged with +1 net charge) and one negatively charged moiety having asingle negative charge functional group (i.e., the negatively chargedmoiety is charged with −1 net charge). In certain embodiments, the saltadduct comprises one positively charged moiety having two positivelycharged functional groups, which may be the same or different (i.e., thepositively charged moiety is charged with +2 net charge) and twonegatively charged moieties, which may be the same or different, andeach having a single negative charged functional group (i.e., eachnegatively charged moiety is charged with −1 net charge). In certainembodiments, the salt adduct comprises two positively charged moieties,which may be the same or different, having each one positively chargedfunctional group (i.e., each positively charged moiety is charged with+1 net charge) and one negatively charged moiety, having two negativelycharged functional groups, being the same or different (i.e., thenegatively charged moiety is charged with −2 net charge). In certainembodiments, the salt adduct comprises a positively charged moietycharged with +n net charge (originating from one or more positivelycharged functional groups, which may be the same or different), and anegatively charge moiety having −n (originating from one or morenegatively charged functional groups, which may be the same ordifferent) net charge, wherein n is an integer which may be equal to 1,2, 3, 4, 5 or 6.

As used herein, a “positively charged moiety of a salt adduct” of theinvention is the corresponding acid of pyridoxine, or any derivativethereof. In certain embodiments, the positive charge of the positivelycharged moiety stems from the protonated basic nitrogen atom ofpyridoxine (as for example in compound (2)) or any derivative thereof(such as for example compounds of formula (I)). In certain embodiments,the positively charged pyridoxine derivative is substituted with apositively charged functional group such as for example —NH₃ ⁺, —CH₂NH₃⁺, —NH₂R⁺, —NHR₂ ⁺ (wherein each R is independently a C₁-C₆ alkyl),which may, in some embodiments, be present in addition to the positivelycharged protonated basic aromatic nitrogen atom in the pyridine ring.

As used herein, a “carboxylated 5- to 7-membered lactam ring” of a saltadduct of the invention, is meant to encompass a γ-lactam, δ-lactam orε-lactam rings, having a negatively charged carboxylate group (—COO⁻)substituted thereto. In certain embodiments, said carboxylate group issubstituted at the lactam ring carbon atom adjacent to the amidenitrogen. In another embodiment said carboxylated lactam ring is aL-2-pyrrolidone-5-carboxylate (compound (1)). In other embodiments saidcarboxylate group is substituted on any position of the lactam ring. Incertain embodiments, said carboxylated 5- to 7-membered lactam ring maybe substituted by another substituent at any position on the lactamring.

It should be understood that the present invention encompasses a saltadduct as described herein above and below, provided that when saidcarboxylated lactam ring is an L-2-pyroglutamate, i.e. compound (1),said positively charged moiety is other than pyridoxine, i.e. compound(2).

In some embodiments of the present invention, said positively chargedmoiety of a salt adduct of the invention, is a compound of formula (I):

-   -   wherein    -   R₁ is straight or branched C₁-C₆ alkyl;    -   R₂ is selected from —OH, straight or branched C₁-C₆ alkoxy, and        straight or branched C₁-C₆ alkoxycarbonyl;    -   R₃ and R₄ are each independently selected from a formyl group,        straight or branched C₁-C₆ alkyl optionally substituted by at        least one halogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆        alkoxycarbonyl.

In certain embodiments, said carboxylated lactam ring of a salt adductof the invention is selected from the group consisting of:

-   -   wherein    -   R₆ is selected from H, straight or branched C₁-C₆ alkyl        optionally substituted by one or more halogen atoms, straight or        branched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl,        cycloalkyl, aryl and heteroaryl optionally substituted by C₁-C₆        alkyl;    -   R₇, R₈, R₉, R₁₀ R₁₁, R₁₂, R₁₃ and R₁₄ are each independently        selected from H, straight or branched C₁-C₆ alkyl, C₂-C₆        alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryl        optionally substituted by at least one group selected from C₁-C₆        alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,        aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆        alkoxycarbonylalkyl and amidino.

In certain embodiments, said carboxylated lactam ring is a compound offormula (II):

wherein R₆, R₇, R₈, R₉ and R₁₀ are as defined above. In certainembodiments, R₆ is C₁-C₆ alkyl. In yet further embodiments, R₉ is C₁-C₆alkyl.

In certain embodiments, said carboxylated lactam ring of a salt adductis a compound of formula (II):

and said positively charged moiety of a salt adduct is compound (2):

wherein R₆, R₇, R₈, R₉ and R₁₀ are as defined above.

In certain embodiments, said carboxylated lactam ring of a salt adductis compound (1):

and said positively charged moiety of a salt adduct is a compound offormula (I):

wherein R₁, R₂, R₃ and R₄ are as defined above.

In some embodiments of the above defined salt adduct of the carboxylatedlactam ring formula (1) and positively charged compound of formula (I),R₁ is a C₁-C₆ alkyl and R₂, R₃ and R₄ are as defined above. In otherembodiments of the above defined salt adduct of the carboxylated lactamring formula (1) and positively charged compound of formula (I), R₂ isselected from hydroxyl and C₁-C₆ alkoxy; and R₁, R₃ and R₄ are asdefined above. In further embodiments of the above defined salt adductof the carboxylated lactam ring formula (1) and positively chargedcompound of formula (I), R₃ is —CH₂R₁₅, wherein R₁₅ is selected from—C₁-C₆ alkoxy, —OH and —NH₃ ⁺; and R₁, R₂ and R₄ are as defined above.In yet further embodiments of the above defined salt adduct of thecarboxylated lactam ring formula (1) and positively charged compound offormula (I), R₄ is selected from formyl and —CH₂R₁₆, wherein R₁₆ isselected from —C₁-C₆ alkoxy and —OH; and R₁, R₂ and R₃ are as definedabove.

In other embodiments of a salt adduct of the invention, saidcarboxylated lactam ring is a compound of formula (III):

and

-   -   said positively charged moiety is a compound of formula (I):

-   -   wherein R₁, R₂, R₃, R₄, R₆, R₇, R₈, R₉, R₁₀, R₁₁ and R₁₂ are as        defined above.

On other embodiments of a salt adduct of the invention, saidcarboxylated lactam ring is a compound of formula (IV):

and

-   -   said positively charged moiety is a compound of formula (I):

-   -   wherein R₁, R₂, R₃, R₄, R₆, R₇, R₈, R₉ R₁₀, R₁₁, R₁₂, R₁₃ and        R₁₄ are as defined above.

In one embodiment of the above defined salt adducts said positivelycharged moiety is a compound of formula (2):

In certain embodiments, the salt adduct is selected from:

(two pyroglutamate moieties).

The term “halogen” as used herein means F, Cl, Br or I.

The term “C₁-C₆ alkyl” as used herein represents a saturated, branchedor straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms.Typical C₁₋₆ alkyl groups include, but are not limited to, methyl,ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, isohexyl and the like.

The term “C₂-C₆ alkenyl” as used herein represents a branched orstraight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and atleast one double bond positioned between any two carbons of the chain.Examples of such groups include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl,2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.

The term “C₂-C₆ alkynyl” as used herein represents a branched orstraight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and atleast one triple bond positioned between any two carbons of the chain.Examples of such groups include, but are not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,1-hexynyl, 2-hexynyl and the like.

The term “C₁-C₆ alkoxy” as used herein refers to the radical —O—C₁₋₆alkyl, wherein C₁₋₆ alkyl is as defined above. Representative examplesare methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy,tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.

The term “C₁-C₆ alkylthio” as used herein refers to the radical —S—C₁₋₆alkyl, wherein C₁₋₆ alkyl is as defined above. Representative examplesare methylthio, ethylthio, isopropylthio, n-propylthio, butylthio,pentylthio and the like.

The term “cycloalkyl” as used herein represents a monocyclic,carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may alsoinclude heteroatoms such as N, O and/or S. Representative examples arecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl and the like.

The term “aryl” as used herein is intended to include carbocyclicaromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl,phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.Aryl is also intended to include the partially hydrogenated derivativesof the carbocyclic systems enumerated above. Non-limiting examples ofsuch partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl,1,4-dihydronaphthyl and the like.

The term “heteroaryl” as used herein refers to ring systems in which atleast one ring is an aromatic ring in which at least one atom is anon-carbon atom, either substituted or non-substituted, where thenon-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.

The term “C₁-C₆ alkoxycarbonyl” as used herein refers to the radical—C(O)O—C₁₋₆ alkyl, wherein C₁₋₆ alkyl is as defined above.

The terms “C₁-C₆ alkoxy” and “C₁-C₆ alkylthio” as used herein refers tothe radicals C₁₋₆—O— and C₁₋₆—S—, respectively, wherein C₁₋₆ alkyl is asdefined above.

The term “hydroxyl” as used herein refers to the radical —OH. As usedherein the term “thiol” refers to the radical —SH. As used herein theterm “formyl” refers to the radical —COH. As used herein the term“cyano” refers to the radical —CN. As used herein the term “nitro”refers to the radical —NO₂.

The term “amine” as used herein refers to —NH₃ or any primary (—NH₂R),secondary (—NHR₂), tertiary (—NR₃) or quarternary amines (—NR₄ ⁺),wherein each R may be the same or different and independently selectedfrom H, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl as defined hereinabove.

The term “C₁-C₆ carboxyalkyl” as used herein refers to the radical—CO—(C₁-C₆ alkyl), wherein C₁₋₆ alkyl is as defined above.

The term “aminocarbonyl” as used herein refers to the radical —CONR₂,wherein each of groups R is independently selected from H, C₁-C₆ alkyl,C₁-C₆ alkenyl, C₁-C₆ alkynyl as defined herein above.

The term “alkoxycarbonylalkyl” as used herein refers to the radical—OCO—(C₁-C₆alkyl), wherein C₁₋₆ alkyl is as defined above.

The term “amidino” as used herein refers to the radical —C(═NH)—NH₂.

The term “optionally substituted” as used herein means that the moietiesreferred to are either unsubstituted or substituted with one or more ofthe substituents specified. When the moieties referred to aresubstituted with more than one substituent the substituents may be thesame or different.

Such substituents can include, for example, a halogen, a hydroxyl, acarbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl),a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate),an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, aphosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro,an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, asulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or anaryl or heteroaryl moiety.

It should be understood that moieties of a salt adduct of the inventionmay contain each at least one chiral center, and thus may exist in, andbe isolated as, any stereoisomer thereof including, enantiomers,diastereomers or any mixtures thereof including, but not limited toracemic mixtures. The present invention includes any possiblestereoisomer (e.g. enantiomers, diastereomers), any mixtures thereofincluding, but not limited to, racemic mixtures, of any of theindividual moieties of a salt adduct of the invention. Where theherein-described processes for the preparation of each of the moietiesof a salt adduct of the invention give rise to mixtures ofstereoisomers, these isomers may be separated by conventionaltechniques, such as preparative chromatography. The moieties of a saltadduct of the invention may be each prepared in any mixture of possiblestereoisomers thereof, including but not limited to racemic mixturesthereof, or individual stereoisomers (e.g. enantiomers, diastereomers)may be prepared either by enantiospecific synthesis or by chiralchromatographic separation of a racemate. Whenever referring to aminoacids, the invention should be understood to encompass natural andnon-natural amino acids or any derivative thereof.

The term “non-natural amino acid” as used herein refers herein to aminoacids, or any derivative thereof, that are not among the amino acidswhich are the building blocks of proteins having L as well asD-configurations, while “natural amino acids”, refer to amino acids orany derivative thereof, which are the building blocks of proteins,having L as well as D-configurations.

Carboxylated 5- to 7-membered lactam rings, which may be optionallysubstituted as defined hereinabove, may be synthetically prepared by anymethod known to a person skilled in the art or by methods describedherein. In certain embodiments, said carboxylated lactam may be preparedfrom the corresponding amino acids, such as by methods described herein.

In one aspect, the invention provides methods of preparing, e.g.,carboxylated lactam ring of formula (II) (e.g. wherein n=1 for areactant of formula (IVa) in Scheme 1), carboxylated lactam ring (III)(e.g. wherein n=2 for a reactant of formula (IVa) in Scheme 1) andcarboxylated lactam ring of formula (IV) (e.g. wherein n=3 for areactant of formula (IVa) in Scheme 1), starting from an amino dioicacid of formula (IVa), as depicted in examplery Scheme 1. It should benoted that the amino dioic acid of formula (IVa) may be in the (R) or(S) configuration or any mixture thereof, such as for example theequimolar racemic mixture.

In another aspect, the invention provides methods of syntheticallypreparing, e.g., carboxylated lactam ring of formula (II) (e.g. whereinn=2 for a reactant of formula (IVb) in Scheme 2), carboxylated lactamring of (III) (e.g. wherein n=3 for a reactant of formula (IVb) inScheme 2) and carboxylated lactam ring of formula (IV) (e.g. wherein n=4for a reactant of formula (IVb) in Scheme 2), as depicted in Scheme 2.

In another aspect, the invention provides methods of preparing a saltadduct including a positively charged pyridoxine moiety, or a derivativethereof, and a carboxylated 5- to 7-membered lactam ring, including thesteps of:

(a) suspending an optionally substituted amino dioic acid in water andheating for a sufficient period of time to allow completinglactamization reaction;

(b) optionally decolorizing the reaction mixture to eliminateimpurities;

(c) isolating the lactam carboxylate;

(d) optionally purifying the obtained lactam carboxylate bycrystallization;

(e) admixing the obtained lactam carboxylate and a pyridoxine base or aderivative thereof in a solvent mixture optionally under heating; and

(f) isolating the product.

In some embodiments of a process of the invention, as described hereinabove, a decolorizing of step (b) may be carried out by using adecolorizing agent such as activated carbon.

In certain embodiments of a process of the invention, as describedherein above, a crystallization of step (d) may be carried out bydissolving the product in an organic solvent and precipitating thepurified product by cooling. The solvent used in step (d) may include analcohol such as, e.g., methanol, ethanol, isopropanol, n-butanol or aketone such as acetone or methyl ethyl ketone, or a mixture of solventsthereof.

In certain embodiments, a solvent mixture of step (e) includes a mixtureof an alcohol such as methanol, ethanol, isopropanol and the like, andwater.

According to yet another embodiment, there is provided methods ofpreparing N-substituted L-pyroglutamic acid and the carboxylate thereof,such as, for example, N-methyl-L-pyroglutamic acid(1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethylester, as depicted in Scheme 3 below.

The invention further provides methods of preparing a salt adduct of theinvention, wherein said positively charged moiety is a substitutedpyridoxine, as depicted in Scheme 4 below. The starting reagent is2-methyl-3-hydroxy-4-methoxymethyl-5-hydroxymethyl-pyridinehydrochloride (Compound (V)). The preparation of the corresponding saltis described in Example 1.

The invention further provides methods of preparing a salt adduct of theinvention, wherein said positively charged moiety is a substitutedpyridoxine, as depicted in Scheme 5 below. The starting reagent inscheme 5 is 2-methyl-3-hydroxy-4-methoxymethyl-5-hydroxymethyl-pyridinehydrochloride (Compound V). The preparation of the corresponding salt isdescribed in Example 2.

Table 1 depicts several examples of salt adducts of the presentinvention.

TABLE 1 Structural formula Salt No.

IId

IIe

IIId

IIa

IIb

IIc

The salt adducts of the invention may be useful, e.g., for preventing,treating or ameliorating one or more various diseases, conditions ordisorders, particularly those associated with or inflicted by alcoholconsumption. The expression “associated with” as used herein includes“caused by” or “linked to” or “(usually) occurring together” or“believed to have an impact on” or otherwise linked.

When referring to diseases, conditions or disorders associated with orinflicted by alcohol consumption, it should be understood to encompassany disease, condition or disorder which is associated with any amountor level of alcohol consumption by a subject, including, for example, aminimal amount of alcohol consumption, a moderate amount of alcoholconsumption or an excessive amount of alcohol consumption. Additionally,said alcohol consumption may be, for example, sporadic, occasional,continuous, sustained or chronic (or alcohol dependence) over any periodof time. In certain embodiments, alcohol consumption by a subjectincludes, but is not limited to social drinking, session drinking orbinge drinking.

Diseases, conditions or disorders associated with or inflicted byalcohol consumption at any of the above amounts or levels, include butare not limited to: alcohol intoxication, alcoholism, cardiovasculardisease, hypertension, coronary heart disease, ischemic stroke, nutrientmalabsorption, chronic pancreatitis, liver diseases (such as, forexample, fatty liver, hepatitis and cirrhosis), cancer, damage to thecentral nervous system, damage to peripheral nervous system, malignantneoplasms, psychiatric disorders (such as for example major depression,dysthymia, mania, hypomania, panic disorder, phobias, generalizedanxiety disorder, personality disorders, schizophrenia, suicide andbrain damage).

In another one of its aspects the invention provides a pharmaceuticalcomposition comprising a salt adduct of the invention.

In another aspect of the invention there is provided a pharmaceuticalcomposition comprising a salt adduct of the invention, for use in thetreatment or prevention of a disease or disorder associated with orinflicted by alcohol consumption. In some embodiments saidpharmaceutical composition comprising a salt adduct of the invention, isintended for use in shortening the half-life of ethanol in the blood ofa subject.

In another one of its aspects the invention provides a use of a saltadduct according to the invention, for the preparation of apharmaceutical composition for the treatment or prevention of a diseaseor disorder associated with or inflicted by alcohol consumption. In someembodiments, said disease or disorder is selected from alcoholintoxication, alcoholism, cardiovascular disease, hypertension, coronaryheart disease, ischemic stroke, nutrient malabsorption, pancreatitis,liver diseases, cancer, CNS damage, neuropsychiatric or neurologicalimpairment, neoplasms and psychiatric disorders or any combinationthereof.

In another aspect, the invention provides a use of a salt adduct of theinvention, for the preparation of a pharmaceutical composition capableof shortening the half-life of ethanol in the blood of a subject.

When referring to the shortening the half-life of ethanol in the bloodof a subject, it should be understood to encompass the ability of a saltadduct of the invention and pharmaceutical compositions comprising it toreduce the time ethanol is cleared from a subject's blood by any amount.The effects of ethanol half-life in the blood may result for example infaster onset of recovery from alcohol intoxication as compared withnon-medicated recovery from alcohol intoxication.

The invention further provides a method for treating or preventing adisease or disorder associated with or inflicted by alcohol consumption,comprising administering to a subject in need thereof an effectiveamount of a salt adduct of the invention. In some embodiments of amethod described herein said disease or disorder is selected fromalcohol intoxication, alcoholism, cardiovascular disease, hypertension,coronary heart disease, ischemic stroke, nutrient malabsorption,pancreatitis, liver diseases, cancer, CNS damage, neuropsychiatric orneurological impairment, neoplasms and psychiatric disorders or anycombination thereof.

In yet a further aspect of the invention, there is provided a method ofshortening the half-life of ethanol in the blood of a subject,comprising administering to a subject in need thereof an effectiveamount of a salt adduct of the invention.

In certain aspects, the invention provides a method for decreasing orpreventing symptoms or effects of alcohol consumption in a subject inneed thereof. In some embodiment of a method of the invention, saidsubject has not reached intoxication, and said method comprisesadministering a composition comprising a salt adduct according to theinvention. In certain aspects, the invention provides a method forpreventing alcohol intoxication in a subject in need thereof, comprisingadministering a composition comprising a salt adduct according to theinvention. Additional methods of treating a subject are disclosed in PCTPublication No. WO2009004629, incorporated herein by reference.

In any of the various embodiments of the methods of the inventiondescribed above, the composition may comprise a salt adduct according tothe invention formulated for immediate release, sustained release,controlled release, or a combination of any of the foregoing. In any ofthe various embodiments of the above described methods, theadministration is non-chronic administration. In certain embodiments, asalt adduct according to the invention is formulated for non-chronicadministration, and preferably for non-invasive administration. Incertain other aspects, the invention provides a method for increasingthe mean t_(max) of a salt adduct according to the invention in theblood of a subject in need thereof comprising administering a saltadduct according to the invention of the invention formulated forsustained release or controlled release, optionally including a portionof the salt adduct according to the invention formulated for immediaterelease.

In certain aspects, the invention provides a use of any one of thecompositions of the invention in the manufacture of a therapeuticcomposition useful for practicing each of the methods of the inventionas described herein, e.g., for reducing or preventing symptoms oreffects of alcohol consumption; for preventing alcohol intoxication; forreducing or eliminating blood alcohol levels in a subject, or forincreasing the mean t_(max) of a salt adduct according to the inventionin the blood of a subject, among others.

In another aspect of the invention, there is provided a kit for reducingthe effect of alcohol intoxication, comprising at least one containercomprising a salt adduct of the invention, and instructions for usethereof. In some embodiments, said kit further comprises means foradministering said salt adduct.

The present invention also provides delivery devices and kits comprisinga salt adduct or composition according to the invention, and methods fortheir use in the treatment or prevention of alcohol consumption relatedsymptoms. Kits may optionally include means for measuring or monitoringblood alcohol concentration (BAC) levels before, during or afteradministration of a salt adduct according to the invention.

The term “treatment” as used herein refers to therapeutic treatment.Those in need of treatment are mammalian subjects suffering from anypathologic condition, particularly conditions associated with excessivealcohol consumption or induced by alcohol. By “patient” or “subject inneed” is meant any mammal who may be affected by the above-mentionedconditions, and to whom the treatment methods herein described aredesired, particularly humans.

Administration of one or more compounds or compositions of the inventionto the patient includes both self-administration and administration tothe patient by another person.

The active ingredient(s) used by the invention or any compositionthereof, may be administered via any mode of administration, forexample, buccal, nasal, oral, inhalation, intravenous, intramuscular,subcutaneous, intraperitoneal, parenteral, transmucosal, transdermal,intravaginal, intranasal, mucosal, sublingual, topical, rectal orsubcutaneous administration, or any combination thereof. Suitable modesof administration are well known in the art and may be selected by theskilled practitioner in view of the subject and condition to be treated.

The term “therapeutically effective amount” as used herein is intendedto mean that amount of a drug or pharmaceutical agent that will elicitthe biological or medical response of a tissue, a system, animal orhuman that is being sought by a researcher, veterinarian, medical doctoror other clinician.

Specific therapeutically effective amounts of the drug administereddaily or otherwise by the methods of the invention may range from about0.005 mg/kg to about 40 mg/kg of body weight, specifically, betweenabout 0.01 to 35 mg/kg, about 0.05 to 30 mg/kg, or about 0.1 to 20mg/kg. In certain embodiments, the effective amount may be about 1,about 10, about 100, or about 1500 mg, preferably, per day. Theeffective amount may be about 5 to 1200 mg per day, such as, forexample, about 10, about 100, about 500, or about 1000 mg per day. Incertain embodiments, the effective amount may be about 1, about 10,about 100, about 200, about 300, about 400, about 500, about 600, about700, about 800, about 900, about 1000, about 1100, about 1200, about1300, about 1400, or about 1500 mg, preferably, per day. It should beappreciated that such effective amount may be specific for a humansubject. These “human doses” may be calculated by dividing doses (mg/kg)in mice by, for example, about 12 to derive respective Human EquivalentDoses (HED) (mg/kg), and further divided by, for example, 10 (SafetyFactor in extrapolating from mice to human), in accordance with theGuidance for Industry, Estimating the Maximum Safe Starting Dose inInitial Clinical Trials for Therapeutics in Adult Healthy Volunteers.[Food and Drug Administration (FDA) and Center for Drug Evaluation andResearch (CDER), July (2005)]. The effective amount of the drug ispreferably comprised within a dosage unit form. Additionally, theadministration of the drugs according to the invention may beperiodical, for example, the periodic administration may be effectivetwice daily, three times daily or at least once daily for at leastabout, for example, two days, three days, four days, five days, six day,seven days or more to one month, two months, three months, four months,or more. There may be advantages of lower doses, evident to those ofskill in the art, that may include, for example, inter alia, a lowerrisk of side effects, especially in long-term use, and a lower risk ofthe patients' becoming desensitized to the treatment.

In certain embodiments, unit dosage forms used according to inventionmay be either for a single or for repeated administration.Administration of said dosage unit form may be repeated, for example,about every one to about five, about ten or about twenty four hours,e.g., for a therapeutically sufficient period of time. In certainembodiment, the unit dosage form may be a sustained-released dosage unitform which provides continued pH-independent drug release for aconsiderable period of time after administration, e.g., 30 minutes, 1hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9hours, 10 hours, 11 hours, or 12 hours or more.

The skilled medical practitioner will appreciate that the treatment ofdifferent conditions may necessitate the use of different doses and/ordifferent dosage regiments.

Therapeutic formulations may be administered in any conventional dosageformulation. Formulations typically comprise at least one activeingredient, as defined herein, together with one or more acceptablecarriers thereof.

The compositions of the invention may comprise a buffering agent, anagent which adjusts the osmolarity thereof, and optionally, one or morepharmaceutically acceptable carriers, excipients and/or additives asknown in the art. Supplementary active ingredients may also beincorporated into the compositions. The carrier may be solvent ordispersion medium containing, for example, water, ethanol, polyol (forexample, glycerol, propylene glycol, and liquid polyethylene glycol, andthe like), suitable mixtures thereof, and vegetable oils. The properfluidity may be maintained, for example, by the use of a coating, suchas lecithin, by the maintenance of the required particle size in thecase of dispersion and by the use of surfactants.

As used herein “pharmaceutically acceptable carrier” may include anysolvent, dispersion media, coatings, antibacterial and antifungal agentsand the like. The use of such media and agents for pharmaceutical activesubstances is well known in the art. Except as any conventional media oragent is incompatible with the active ingredient, its use in thetherapeutic composition is contemplated.

Compounds or compositions of the invention (including pharmaceuticalcompositions, “drugs”) may be administered orally. The active compoundsor compositions of the invention employed in therapy may be administeredin various oral forms including, but not limited to, tablets, capsules,pills, lozenges, powders, granules, elixirs, tinctures, suspensions,syrups, and emulsions. The compounds or compositions of the inventionmay be delivered by any pharmaceutically acceptable route and in anypharmaceutically acceptable dosage form. These include, but are notlimited to the use of oral conventional rapid-release, timecontrolled-release, and delayed-release pharmaceutical dosage forms. Theactive drug components may be administered in a mixture with suitablepharmaceutical diluents, excipients or carriers (collectively referredto herein as “carrier” materials) suitably selected to with respect tothe intended form of administration.

In instances in which the composition for oral administration is in theform of a tablet or capsule, the compounds or compositions of theinvention may be combined with a non-toxic pharmaceutically acceptableinert carrier such as lactose, starch, sucrose, glucose, modifiedsugars, modified starches, methylcellulose and its derivatives,dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and otherreducing and non-reducing sugars, magnesium stearate, stearic acid,sodium stearyl fumarate, glyceryl behenate, calcium stearate and thelike. For oral administration in liquid form, the compounds orcompositions of the invention may be combined with non-toxicpharmaceutically acceptable inert carriers such as ethanol, glycerol,water and the like. When desired or required, suitable binders,lubricants, disintegrating agents and coloring and flavoring agents mayalso be incorporated into the mixture. Stabilizing agents such asantioxidants, propyl gallate, sodium ascorbate, citric acid, calciummetabisulphite, hydroquinone, and 7-hydroxycoumarin may also be added tostabilize the dosage forms. Other suitable compounds may includegelatin, sweeteners, natural and synthetic gums such as acacia,tragacanth, or alginates, carboxymethylcellulose, polyethylene, glycol,waxes and the like.

Alternatively, the compounds or compositions of the invention may beadministered in controlled release formulations such as a slow releaseor a fast release formulation. Such controlled release formulations maybe prepared using methods known to those skilled in the art. The methodof administration may be determined by the attending physician or otherperson skilled in the art after an evaluation of the subject's conditionand requirements.

For purposes of parenteral administration, solutions in sesame or peanutoil or in aqueous propylene glycol may be employed, as well as sterileaqueous solutions of the corresponding water-soluble salts. Such aqueoussolutions may be suitably buffered, if necessary, and the liquid diluentfirst rendered isotonic with sufficient saline or glucose. These aqueoussolutions may be especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal injection purposes. The sterile aqueousmedia employed may be readily obtainable by standard techniques known tothose skilled in the art. Methods of preparing various pharmaceuticalcompositions with a certain amount of active ingredient are known, orwill be apparent in light of this disclosure, to those skilled in thisart.

The invention further provides a method for preventing or reducing therisk of developing a disease, disorder or pathological conditionsassociated with or inflicted by alcohol consumption. Such methodcomprises the administration of a prophylactically effective amount ofat least one compound of the invention or of any composition comprisingthe same, to a person at risk of developing any of the said conditions.

The term “prophylactically effective amount” as used herein is intendedto mean that amount of a the drug of the invention or a pharmaceuticalcomposition comprising the same, that will prevent or reduce the risk ofoccurrence or recurrence of the biological or medical event that issought to be prevented in a tissue, a system, animal or human.

It should be noted that for the methods of treatment and preventionprovided in the present invention, the therapeutically effective amount,or dosage, may be dependent on the severity and responsiveness of thedisease state to be treated, with the course of treatment lasting from,for example, several days to several months, or until a cure is effectedor a diminution of the disease state is achieved. Optimal dosingschedules may be calculated from measurements of drug accumulation inthe body of the patient. Persons of ordinary skill can easily determineoptimum dosages, dosing methodologies and repetition rates. In general,dosage is calculated according to body weight, and may be given once ormore daily, weekly, monthly or yearly, or even once every 2 to 20 years.Persons of ordinary skill in the art may easily estimate repetitionrates for dosing based on measured residence times and concentrations ofthe compounds of the invention or any composition of the invention inbody fluids or tissues. Following successful treatment, it may bedesirable to have the patient undergo maintenance therapy to prevent therecurrence of the disease state, wherein the combined composition of theinvention is administered in maintenance doses, once or more daily.

According to another aspect, the invention relates to the use of atherapeutically effective amount of at least one compound or compositionof the invention or any combination or mixture thereof, in thepreparation of a medicament for the treatment or prevention of adisorder, disease or condition associated with or inflicted by alcoholconsumption, particularly excessive alcohol consumption as describedherein.

It should be noted that where the drug is formulated in an entericcoated dosage form, a substantial release of the compound from thedosage form after oral administration to a patient may be delayed untilpassage of the dosage form through the stomach.

It is to be understood that the invention is not limited to theparticular examples, process steps, and materials disclosed herein assuch process steps and materials may vary.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising” “having” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein may be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

Certain embodiments of this invention are described herein. Variationsof certain embodiments may become apparent to those of ordinary skill inthe art upon reading the foregoing description. The inventors expectskilled artisans to employ such variations as appropriate, and theinventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

The redwerences in this specification to any prior publication (orinformation derived thereof), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived thereof)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Reference is now made to the following examples, which together with theabove description, serve to illustrate the invention but without in anyway limiting its scope. The following Examples are representative oftechniques employed by the inventors in carrying out aspects of thepresent invention. It should be appreciated that while these techniquesare exemplary of preferred embodiments for the practice of theinvention, those of skill in the art, in light of the presentdisclosure, will recognize that numerous modifications may be madewithout departing from the spirit and intended scope of the invention.

EXAMPLES Example 1 Preparation of pyridoxamine,L-2-pyrrolidone-5-carboxylate (Salt IId) Preparation of Pyridoxine FreeBase

1.2 g (5 mmol) of pyridoxamine dihydrochloride (Aldrich) was dissolvedin 6 mL water in an Erlenmeyer and a solution of 1 g sodium bicarbonate(12 mmol) in 15 mL water was added with liberation of CO₂. The solutionwas cooled to 0° C. to afford crystallization. After some time, theprecipitated crystals were collected by filtration, washed with coldwater and dried to yield 0.73 g (87%) of the pyridoxamine free base.

Preparation of L-Pyroglutamic Acid

20 g of monosodium glutamate (Aldrich) was mixed with 11 mL of HCl 32%and the pH was adjusted to about 2.5 (using HCl). The mixture was heatedto above 100° C. in an autoclave for 10 hours. Then, the solution wasevaporated to dryness to obtain the L-pyroglutamic acid.

Preparation of the Salt

313 mg of L-pyroglutamic acid (2.43 mmol) was dissolved under heating atabout 40° C. in about 4 mL ethanol followed by addition of 409 mg (2.43mmol) of the free pyridoxamine base (as obtained above) to give a clearsolution. The solution was left aside for 3 hours at ambient temperatureto give a solid mass. In order to enable mixing, additional 2 mL ofethanol was added and the crystals were cooled for half an hour in icecold water, collected by filtration, washed with cold ethyl alcohol anddried to yield 600 mg of Salt IId in 83% yield.

¹H NMR (DMSO-d₆), δ ppm: 1.9 (m, 1H), 2.1 (m 2H), 2.3 (m, 1H), 2.4 (s,3H), 2.5 (s, 1H), 4.1 (m, 1H), 4.9 (s, 2H), 7.8 (s, 1H), 8.2 (s, 1H)

Example 2 Preparation of3-hydroxy-5-(hydroxymethyl)-2-methylisonicotinealdehyde-mono ethylacetal, L-2-pyrrolidone-5-carboxylate (Salt IIe) Preparation ofPyridoxal Free Base

1.016 g (5 mmol) of pyridoxal hydrochloride (Aldrich) was placed in anErlenmeyer and a solution of 0.456 g sodium bicarbonate (5.4 mmol) in 5mL water was added. The resulting solution was set aside for some timeand crystals precipitated. The thus precipitated crystals were collectedby filtration, washed with cold water and dried to afford 0.68 g of thepyridoxal free base (80% yield).

Preparation of the Salt

471 mg (2.8 mmol) of the pyridoxal free base was dissolved in a mixtureof 16.5 mL ethanol and 3.5 mL water and heated to about 60° C., followedby addition of 364 mg (2.8 mmol) of L-pyroglutamic acid to give a clearsolution. The solution is left aside and several portions of ethanolwere added followed by drying of the solution to dryness to yield 930 mgof Salt IIe as hemiacetal in 93% yield.

¹H NMR (D₂O), 6 ppm: 1.3 (t, 3H), 2.1 (m 1H), 2.4 (m, 2H), 2.5 (m, 1H),2.6 (s, 3H), 3.7 (q, 2H), 4.3 (m, 1H), 4.7 (s, 2H), 6.7 (s, 1H), 8.1 (s,1H).

Example 3 Preparation of pyridoxine, (S)-oxo-2-piperidine carboxylate(Salt IIId)

169.2 mg of pyridoxine free base (1 mmol) and 143.1 mg of(S)-oxo-2-piperidine carboxylic acid (1 mmol) (Aldrich) were weighedinto a vial and mixed with about 0.2 mL of a solution of isopropylalcohol containing 4.4% water. The mixture was heated in the closed vialto a temperature of about 35° C. The mixture was gradually cooled toroom temperature overnight. Then, about 2.5 mL of isopropyl alcohol wasadded under boiling to give a clear solution, and the solution was leftto cool to room temperature. Diethyl ether was added and the mixture wasmaintained at a temperature of about −18° C. to afford crystallization.The crystals were obtained by filtration, washed with cold isopropylalcohol and dried to yield 270 mg of Salt IIId in 86% yield.

¹H NMR (D₂O), δ ppm: 1.1 (m, 2H), 1.7 (m, 1H), 2.0 (m, 1H), 2.3 (t, 2H),2.5 (s, 3H), 3.9 (m 1H), 4.7 (s, 2H), 4.9 (s, 2H), 8.0 (s, 1H).

Example 4 Preparation of pyridoxine,L-2-pyrrolidone-4-methyl-5-carboxylate (Salt IIa) Preparation ofL-2-pyrrolidone-4-methyl-5-carboxylate

25 g of chemically pure (2S,3S)-3-methyl glutamic acid are suspended in25 mL of water in an autoclave and heated at 140° C. for 5 hours. Thewarm solution is decolorized with activated carbon and cooled graduallyto room temperature and then to 4° C., during which time a precipitateis formed. The precipitate is isolated by filtration and crystallizedfrom acetone to obtain white crystals.

Preparation of the Salt

14.3 g of L-2-pyrrolidone-4-methyl-5-carboxylate produced as describedabove and 16.9 g of pyridoxine base are thoroughly sieved and mixed forhalf an hour. A solution containing 86 mL isopropanol and 4 mL deionizedwater is added to the mixture and the resulting solution is stirred forhalf an hour at 35° C. during which time a thick solid is obtained. Thethus formed solid is filtered off and vacuum dried at 38° C. for 24hours. The resulting solid is dissolved in about 60 mL of boilingisopropanol and the mixture is allowed to reach 38° C. to enablecrystallization. The thus formed crystals are filtered off and vacuumdried at 38° C. for additional 24 hours to obtain solid Salt IIa.

Example 5 Preparation of pyridoxine,N-methyl-L-2-pyrrolidone-5-carboxylate (Salt IIb)

L-pyroglutamic acid ethyl ester (10 g, 0.07 mole) is dissolved intetrahydrofuran (100 mL) and cooled to 0° C. Sodium hydride (2 g, in a60% suspension in oil, 0.084 mole) is added to the mixture, followed byaddition of methyl iodide (5.2 mL, 0.084 mole) under constant mixing.The mixture is allowed to warm up to ambient temperature and mixed foran additional hour. The solvent is evaporated under reduced pressure andwater is added (10 mL). The aqueous layer is extracted withdichloromethane, which is evaporated to yield the crude1-methyl-L-pyroglutamic acid ethyl ester.

The obtained crude 1-methyl-L-pyroglutamic acid ethyl ester is dissolvedin methanol (100 mL) and a solution of 2N sodium hydroxide (35 mL) isadded. The mixture is heated at reflux for 3 hours then cooled and themethanol is evaporated. The resulting aqueous solution is acidified topH 2 using HCl 1M, washed with dichloromethane and evaporated to yield1-methyl-L-pyroglutamic acid.

2.86 g of 1-methyl-L-pyroglutamic acid and 3.38 g of pyridoxine base arethoroughly sieved and mixed for half an hour. A solution containing 20mL isopropanol and 1 mL deionized water is added to mixture and theresulting solution is stirred for half an hour at 35° C. during whichtime a thick solid is obtained. The thus formed solid is filtered offand vacuum dried at 38° C. for 24 hours. The resulting solid isdissolved in about 60 mL of boiling isopropanol and the mixture isallowed to reach 38° C. to enable crystallization. The thus formedcrystals are filtered off and vacuum dried at 38° C. for additional 24hours to obtain Salt IIb.

Example 5A Preparation of 1-methyl-L-pyroglutamic Acid

25 g of chemically pure N-methyl-L-glutamic acid is suspended in 25 mLof water in a autoclave and heated to 140° C. for 5 hours. The warmsolution is decolorized with activated carbon and cooled gradually toroom temperature and then to 4° C., during which time a precipitate isformed. The precipitate is isolated by filtration and crystallized fromacetone to obtain white crystals.

Example 6 Preparation of4,5-bis(ethoxymethyl)-3-ethoxy-2-methyl-pyridine,L-2-pyrrolidone-5-carboxylate (Salt IIc)

Equimolar quantities of pyridoxine, ethyl iodide along with sodiumhydroxide are admixed in an autoclave together with DMF and heated to110° C. for 3 hours. The product is recovered, analyzed by HPLC andpurified.

Equimolar quantities of the purified product and L-pyroglutamic acid arethoroughly sieved and mixed for half an hour. A solution containing 20mL isopropanol and 1 mL deionized water is added to mixture and theresulting solution is stirred for half an hour at 35° C. during whichtime a thick solid is obtained. The thus formed solid is filtered offand vacuum dried at 38° C. for 24 hours. The resulting solid isdissolved in about 60 mL of boiling isopropanol and the mixture isallowed to reach 38° C. to enable crystallization. The thus formedcrystals are filtered off and vacuum dried at 38° C. for additional 24hours to obtain Salt IIc.

Biological Example A Reduction of GSH Activity in Human HepatocellularCarcinoma Cell Line

The efficacy of the salt adducts of the invention is tested according tothe GSH content assay described by Gutiérrez-Ruiz, M. C. et al.[Pharmacological Research, Vol. 44, No. 5, 2001, ibid.]. Humanhepatocellular carcinoma cell line HepG2 are grown in monolayer cultureat 37° C. in disposable plastic bottles in a humidified atmosphere of95% air and 5% CO₂. Twenty-four hours after seeding, culture media arechanged for serum-free media containing ethanol 50 mM and the testedsalts and are incubated for 24 h. Cells are washed twice with PBS andgently scraped into 0.5 mL of PBS. An aliquot is taken to determineprotein. Standard curves are established using known GSH dilutions.Reduced (GSH) is measured by glutathione reductase and NADPH followed byreduction of the colorimetric reagent 5-50-dithio-bis-(2-nitrobenzoicacid) by GSH.

Biological Example B Ethanol Clearance in Animals Treated with SaltAdducts of the Invention

The efficacy of the compounds of the invention is tested according tothe method described by Calabrese, V. et al. in Int. J. Tiss. Reac. XVII(3) 101-108 (1995). Two groups of male Wistar rats weighing 250-300 gare treated with a dose of 2 g/kg body weight of 20% ethanol solutionfor seven days. One group is treated with the tested salt 1 hour beforeethanol administration. The second group serves as a control. At the endof the treatment period, blood samples are removed at different times bycardiac puncture. The blood is centrifuged and plasma samples areanalysed for ethanol content by head-space gas-chromatography. Ethanolconcentrations are calculated based on a standard curve comparing peakheight between standads and tested samples.

1. A salt adduct comprising at least one positively charged moiety beinga pyridoxine or a derivative thereof and at least one carboxylated 5- to7-membered lactam ring, optionally additionally substituted; providedthat when said carboxylated lactam ring is an L-2-pyroglutamate, saidpositively charged moiety is other than pyridoxine.
 2. A salt adductaccording to claim 1, wherein said positively charged moiety is acompound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl. 3.A salt adduct according to claim 1, wherein said carboxylated lactamring is selected from the group consisting of:

wherein R₆ is selected from H, straight or branched C₁-C₆ alkyloptionally substituted by at least one halogen, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁,R₁₂, R₁₃ and R₁₄ are each independently selected from H, straight orbranched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.
 4. A salt adduct according to claim 1,wherein said carboxylated lactam ring is a compound of formula (II):

and said positively charged moiety is compound (2):

R₆ is selected from H, straight or branched C₁-C₆ alkyl substituted byat least one halogen, straight or branched C₂-C₆alkenyl, straight orbranched C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryl optionallysubstituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ are each independentlyselected from H, straight or branched C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by atleast one group selected from C₁-C₆ alkyl, halogen, amino, cyano, nitro,thiol, C₁-C₆ alkoxy, aminocarbonyl, C₁-C₆ alkoxy carbonyl, C₁-C₆carboxyalkyl, C₁-C₆ alkoxycarbonylalkyl and amidino.
 5. A salt adductaccording to claim 1, wherein said carboxylated lactam ring is compound(1):

and said positively charged moiety is a compound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl. 6.A salt adduct according to claim 1, wherein said carboxylated lactamring is compound (1):

and said positively charged moiety is a compound of formula (I):

wherein R₁ is a C₁-C₆ alkyl; R₂ is selected from —OH, straight orbranched C₁-C₆ alkoxy, and straight or branched C₁-C₆ alkoxycarbonyl; R₃and R₄ are each independently selected from formyl, straight or branchedC₁-C₆ alkyl optionally by at least one halogen, amine, hydroxyl, C₁-C₆alkoxy, thiol, C₁-C₆ alkoxycarbonyl.
 7. A salt adduct according to claim1, wherein said carboxylated lactam ring is compound (1):

and said positively charged moiety is a compound of formula (I):

wherein R₂ is selected from —OH and C₁-C₆ alkoxy; and R₁ is straight orbranched C₁-C₆ alkyl; R₃ and R₄ are each independently selected fromformyl, straight or branched C₁-C₆ alkyl optionally substituted by atleast one halogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆alkoxycarbonyl.
 8. A salt adduct according to claim 1, wherein saidcarboxylated lactam ring is compound (1):

and said positively charged moiety is a compound of formula (I):

wherein R₃ is —CH₂R₁₅, wherein R₁₅ is selected from —C₁-C₆ alkoxy, —OHand —NH₃ ⁺; and R₁ is straight or branched C₁-C₆ alkyl; R₂ is selectedfrom —OH, straight or branched C₁-C₆ alkoxy, and straight or branchedC₁-C₆ alkoxycarbonyl; R₄ is selected from formyl, straight or branchedC₁-C₆ alkyl optionally substituted by at least one halogen, amine,hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl.
 9. A salt adductaccording to claim 1, wherein said carboxylated lactam ring is compound(1):

and said positively charged moiety is a compound of formula (I):

wherein R₄ is selected from formyl and —CH₂R₁₆, wherein R₁₆ is selectedfrom —C₁-C₆ alkoxy and —OH; and R₁ is straight or branched C₁-C₆ alkyl;R₂ is selected from —OH, straight or branched C₁-C₆ alkoxy, and straightor branched C₁-C₆ alkoxycarbonyl; R₃ is selected from formyl, straightor branched C₁-C₆ alkyl optionally substituted by at least one halogen,amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl.
 10. A saltadduct according to claim 1, wherein said carboxylated lactam ring is acompound of formula (II):

wherein R₆ is selected from H, straight or branched C₁-C₆ alkyloptionally substituted by at least one halogen, straight or branchedC₂-C₆ alkenyl, straight or branched C₂-C₆ alkenyl, cycloalkyl, aryl andheteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ areeach independently selected from H, straight or branched C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryl optionallysubstituted by at least one group selected from C₁-C₆ alkyl, halogen,amino, cyano, nitro, thiol, C₁-C₆ alkoxy, aminocarbonyl, C₁-C₆alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆ alkoxycarbonylalkyl andamidino.
 11. A salt adduct according to claim 1, wherein saidcarboxylated lactam ring is a compound of formula (II):

wherein R₆ is C₁-C₆ alkyl and R₇, R₈, R₉, R₁₀ are each independentlyselected from H, straight or branched C₁-C₆ allyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, cycloalkyl, aryl and heteroaryl optionally substituted by atleast one group selected from C₁-C₆ alkyl, halogen, amino, cyano, nitro,thiol, C₁-C₆ alkoxy, aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆carboxyalkyl, C₁-C₆ alkoxycarbonylalkyl and amidino.
 12. A salt adductaccording to claim 1, wherein said carboxylated lactam ring is acompound of formula (II):

wherein R₉ is C₁-C₆ alkyl, R₆ is selected from H, straight or branchedC₁-C₆ alkyl optionally substituted by at least one halogen, straight orbranched C₂-C₆ alkenyl, straight or branched C₂-C₆ alkenyl, cycloalkyl,aryl and heteroaryl optionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉,R₁₀ are each independently selected from H, straight or branched C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryloptionally substituted by at least one group selected from C₁-C₆ alkyl,halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy, aminocarbonyl, C₁-C₆alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆ alkoxycarbonylalkyl andamidino.
 13. A salt adduct according to claim 1, wherein saidcarboxylated lactam ring is a compound of formula (III):

and said positively charged moiety is a compound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl R₆is selected from H, straight or branched C₁-C₆ alkyl optionallysubstituted by at least one halogen, straight or branched C₂-C₆ alkenyl,straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryloptionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁, R₁₂, R₁₃and R₁₄ are each independently selected from H, straight or branchedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.
 14. A salt adduct according to claim 1,wherein said carboxylated lactam ring is a compound of formula (IV):

and said positively charged moiety is a compound of formula (I):

wherein R₁ is straight or branched C₁-C₆ alkyl; R₂ is selected from —OH,straight or branched C₁-C₆ alkoxy, and straight or branched C₁-C₆alkoxycarbonyl; R₃ and R₄ are each independently selected from formyl,straight or branched C₁-C₆ alkyl optionally substituted by at least onehalogen, amine, hydroxyl, C₁-C₆ alkoxy, thiol, C₁-C₆ alkoxycarbonyl R₆is selected from H, straight or branched C₁-C₆ alkyl optionallysubstituted by at least one halogen, straight or branched C₂-C₆ alkenyl,straight or branched C₂-C₆ alkynyl, cycloalkyl, aryl and heteroaryloptionally substituted by a C₁-C₆ alkyl; R₇, R₈, R₉, R₁₀ R₁₁, R₁₂, R₁₃and R₁₄ are each independently selected from H, straight or branchedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, cycloalkyl, aryl andheteroaryl optionally substituted by at least one group selected fromC₁-C₆ alkyl, halogen, amino, cyano, nitro, thiol, C₁-C₆ alkoxy,aminocarbonyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ carboxyalkyl, C₁-C₆alkoxycarbonylalkyl and amidino.
 15. (canceled)
 16. A salt adductaccording to claim 1, selected from the following group:


17. A pharmaceutical composition comprising a salt adduct of claim 1.18. (canceled)
 19. (canceled)
 20. (canceled)
 21. (canceled) 22.(canceled)
 23. A method for treating or preventing a disease or disorderassociated with or inflicted by alcohol consumption, comprisingadministering to a subject in need thereof an effective amount of a saltadduct of claim
 1. 24. A method according to claim 23, wherein saiddisease or disorder is selected from alcohol intoxication, alcoholism,cardiovascular disease, hypertension, coronary heart disease, ischemicstroke, malabsorption, pancreatitis, liver diseases, cancer, CNS damage,neuropsychiatric or neurological impairment, neoplasms, psychiatricdisorders or any combination thereof.
 25. A method of shortening thehalf-life of ethanol in the blood of a subject, comprising administeringto a subject in need thereof an effective amount of a salt adduct ofclaim
 1. 26. A kit for reducing the effect of alcohol intoxication,comprising at least one container comprising a salt adduct according toclaim 1, and instructions for use thereof.
 27. (canceled)